Lack of Interaction of Buprenorphine With Flunitrazepam Metabolism

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Abstract
The authors' goal was to determine if the reported clinical adverse interaction of flunitrazepam and buprenorphine was caused by inhibition of drug metabolism. Inhibition of flunitrazepam metabolism by buprenorphine and norbuprenorphine were determined in three human liver microsome preparations carrying the CYP2C19*1/*1 allele. Omeprazole metabolism mediated by CYP2C19 and CYP3A4 was used as a control reaction. Apparent K(i) values were determined. Norbuprenorphine did not inhibit the metabolism of flunitrazepam or omeprazole. Buprenorphine inhibited the formation of CYP3A4-mediated pathways of 3-hydroxyflunitrazepam and omeprazole sulfone formation (K(i) 118 and 16 microM) in human liver microsomes. Corresponding values were 38 and 90 microM in cDNA-expressed CYP3A4 microsomes. Projected in vivo inhibition of CYP3A4-mediated metabolism of flunitrazepam by buprenorphine is 0. 1%-2.5%. Estimated inhibition of buprenorphine N-dealkylation by flunitrazepam in vivo is 0.08%. The clinical interaction of flunitrazepam and buprenorphine is likely based on a pharmacodynamic mechanism.